We are trying to find out how large molecules, like plasma proteins and artificial plasma expanders, get through the walls of capillaries and other small blood vessels, how they are carried through the interstitial spaces of the body, and how they are returned to the bloodstream by the lymphatic vessels. We shall study the action of capillary walls as molecular sieves, and try to relate their function to what is known of their structure. We shall also investigate the properties of the interstitial matrix in various tissues and organs for molecular exclusion. Our approach will be to inject test molecules of known characteristics into the bloodstream of experimental animals (dogs and rats, mostly) and measure their rates of appearance in tissues and in lymph, and the steady-state concentrations reached. We shall also investigate the effects of plasma volume depletion and expansion on large molecule transport.